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Eric R. Kandel - Biographical

Prologue: Life in Vienna in the
1930s
There was little in my early life to indicate that an interest in
biology would become the passion of my academic career. In fact,
there was little to suggest I would have an academic career.
Rather, my early life was importantly shaped by my experiences in
Vienna and I spent many years later coming to grips with the
circumstances and place of my birth.

I was born in Vienna on November 7, 1929,
eleven years after the multiethnic Austro-Hungarian Empire fell
apart following its defeat in World War I. Although Austria had
been radically reduced in size (from 54 million to only 7 million
inhabitants) and in political significance, its capital, the
Vienna of my youth, was still intellectually vibrant, one of the
great cultural centers of the world. A city of one and a half
million people, it was home to Sigmund Freud, Karl Kraus, Robert
Musil, Arthur Schnitzler, and for a while Arnold Schoenberg. The
music of Gustav Mahler and of the earlier 19th Century Vienna
school resonated throughout the city, as did the bold
expressionist images of Gustav Klimt, Oskar Kokoschka, and Egon
Schiele. Even as it thrived culturally, however, Vienna in the
1930s was the capital city of an oppressive, authoritarian
political system. I was too young to appreciate its cultural
richness, but I sensed later, from the perspective of a more
carefree adolescence in the United States, the oppressive
conditions in Vienna that affected my early youth.

Even prior to the Anschluss in 1938,
anti-Semitism was a chronic feature of Viennese life. Jews, who
made up nearly 20% of the city's population, were discriminated
against in the Civil Service and in many aspects of social life.
Nonetheless, they were fascinated by the city in which they had
lived for over a thousand years. My parents genuinely loved
Vienna, and in later years I learned from them why the city
exerted a powerful hold on them and other Jews. My parents loved
the dialect of Vienna, its cultural sophistication, and artistic
values. "The greatest grim irony of all was the fierce attachment
of so many Jews to a city that through the years demonstrated its
deep-rooted hate for them," wrote George Berkley, the American
historian of Vienna and its Jews. This fierce attachment was
considered by the historian Harvey Zohn to be the most tragically
unrequited love in world history.

In spite of the hostile climate, Austrian
Jews continued to make remarkable contributions to theater,
music, literature, science, and medicine in the period between
the two World Wars. The Salzburg Festival was directed by Max
Reinhardt; the Vienna Opera was conducted by Bruno Walter. Stefan
Zweig and Franz Werfel were two of the most popular writers in
the German language, and Elias Canetti, who
later won the Nobel Prize in Literature for books describing his
youth in Vienna, began writing these in the 1930s. Two of the
three Austrians to be awarded the Nobel Prize in Physiology and
Medicine in the 1930s were of Jewish origin: Karl Landsteiner was
honored in 1930 for his discovery of blood groups and Otto Loewi in 1936 for
discovering acetylcholine, a chemical transmitter that slowed the
heart. Of the 52 Olympic medals earned by Austrian athletes from
the beginning of modern Olympics to 1936, 18 were won by Jewish
Austrians. Fully half of the practicing physicians and medical
faculty at the University of Vienna were Jewish. This, in
fact, was the last period during which Viennese medicine still
attracted students and patients from all over the world. They
came to study with, or to be treated by, pioneers in diagnostics
and therapeutic medicine, such as the pediatrician Béla
Schick, the ear specialist Heinrich von Neumann, and the
psychoanalyst Sigmund Freud. As this listing makes clear, the
period of my early youth has been characterized, appropriately,
as "the final flowering of the Austrian Jewish intellectual
activity."

My parents were not born in Vienna, but
they had spent much of their lives there, having each come to the
city at the beginning of World War I when they were still very
young. My mother, Charlotte Zimels, was born in 1897 in Kolomea,
a town of about 43,000 inhabitants in Galicia, a region of the
Austro-Hungarian Empire. (Kolomea now is part of the Ukraine and
has been renamed Kolomyya.) Almost half the population of Kolomea
was Jewish, and the Jewish community had a very active culture.
My mother came from a well-educated middle-class family, and
although she had spent only one year at the university in Vienna,
she spoke and wrote English as well as German and Polish.

My father Herman was born into a poor
family in 1898 in Olesko, a small town of about 3,500 people near
Lvov (Lemberg), now also part of the Ukraine. During World War I
he was drafted into the Austria-Hungarian Army directly from high
school. After the war he worked to support himself and never went
back to school.

My parents met in Vienna and married in
1923, shortly after my father had established himself as the
owner of a small toy store. My brother Lewis was born on November
14, 1924. I was born five years later. We lived in a small
apartment at Severingasse 8 in the 9th district, a middle-class
neighborhood near the medical school, and not too far from
Freud's apartment, although we had no association with either.
Both of my parents worked in the store, and we had a full-time
housekeeper to help out at home.

I went to a school near our house. As with
most elementary schools in Vienna, it was very traditional and
very good, and I followed the well-trodden trail that my
exceptionally gifted brother Lewis had blazed five years earlier
in the same school with the very same teachers. Throughout my
years in Vienna I felt that his was an intellectual virtuosity
that I would never match. By the time I began reading and
writing, he already was starting to master Greek and to play the
piano.

My fondest early memories are of family
get-togethers and vacations. On Sunday afternoons my Aunt Minna
(my mother's sister) and Uncle Srul would come for tea. This was
an occasion for my father and uncle to play cards, games at which
my father excelled and which brought out great animation and
humor in him. We celebrated Passover in a festive way at the home
of my grandparents Hersch and Dora Zimels, and we invariably went
on vacation in August to Monichkirchen, a small farming village
in the southeast portion of Lower Austria, not far from
Vienna.

It was just as we were about to depart for
Monichkirchen in July of 1934 that the Austrian Chancellor,
Engelbert Dollfuss, who had outlawed the Nazi Party, was
assassinated by a band of Austrian Nazis disguised as policemen -
the first political storm to register on my slowly maturing
political awareness. Following the Dollfuss assassination and
during the early years of the chancellorship of his successor,
Kurt von Schuschnigg, the Austrian Nazi Party went further
underground, but it continued nonetheless to gain new adherents,
especially among teachers and other civil servants.
Paradoxically, the Austrian drive toward authoritarianism was
abetted by Dollfuss's own political attitudes and actions.
Modeling himself on both Mussolini and Hitler, Dollfuss renamed
his Christian Socialist Party the Fatherland Front, and
took to wearing a modified swastika. To assure his own control of
the government he abolished Austria's Constitution and outlawed
not only the Nazi Party but all opposition parties. Thus,
although Dollfus opposed the efforts of the Austrian National
Socialist movement to form a Pan-German state with Germany, his
abolition of the Constitution and of other political parties
helped open the door for Hitler to march in.

And, as I well remember, march in he did.
Since his youth, Hitler had dreamed of the union of Austria and
Germany. It is therefore not surprising that a key point in the
Nazi program, from its beginning in the 1920s, was a merger of
all German-speaking people into a Greater Germany. In the fall of
1937 Hitler began to act on this program by raising the level of
rhetoric and threatening to move against Austria. Schuschnigg,
eager to assert Austria's independence, met with Hitler on
February 12, 1938 in Berchtesgaden. Hitler showed up with two of
his generals in tow and threatened to invade Austria unless
Schuschnigg, lifted the legal restrictions on the Austrian Nazi
Party and appointed three Austrian Nazis to key ministerial
positions in the Austrian Cabinet. Schuschnigg refused, but as
Hitler continued to intimidate him, Schuschnigg compromised and
agreed to a legalization of the Nazi party and to granting it two
cabinet positions. The agreement between Schuschnigg and Hitler
so emboldened the Austrian Nazis that they began to challenge the
Austrian government in a series of incidents that the police had
difficulty controlling. Faced with Hitler's aggression from
without and the Austrian Nazi rebellion from within, Schuschnigg
took the offensive on March 9th and boldly called for a
plebiscite on Austria's autonomy to be held four days later, on
March 13th.

This courageous move caught Hitler by
complete surprise, an awkward surprise since it seemed almost
certain that the vote would favor an independent Austria. Hitler
responded by mobilizing troops and threatening to invade Austria
unless Schuschnigg postponed the plebiscite, resigned as
chancellor, and formed a new government with an Austrian Nazi,
Arthur Seyss-Inquart as chancellor. Schuschnigg turned for help
to England and Italy, two countries that had formerly supported
Austrian independence. But on this occasion both countries failed
him and did not respond. Abandoned by his potential allies and
concerned about needless bloodshed, Schuschnigg resigned on the
evening of March 11th. "Austria is yielding to force," he
announced in an emotional farewell radio address to the nation.
"God protect Austria." Even though Schuschnigg had resigned and
President Miklos of Austria gave in to all the German conditions
Hitler nonetheless invaded Austria.

Hitler's triumphal march into Vienna and
his overwhelming reception by the Viennese public made an
indelible impression on me. My brother had just finished building
his first short-wave radio receiver, and on the evening of March
13th we both were listening with earphones as the broadcaster
described the earlier crossing of the Austrian border by German
troops on the morning of March 12th. Hitler followed later in the
afternoon of that day, crossing the border first at Braunnau am
Inn, his native village, and then moving into Linz, the capitol
of Upper Austria, where people welcomed him in the marketplace as
their native son, screaming "Heil Hitler." Of the 120,000 people
of Linz, almost 100,000 came out to greet Hitler. In the
background the Horst Wessel song, one of the hypnotic Nazi
marching songs that even I found captivating, blared forth. On
the afternoon of March 14th Hitler's entourage reached Vienna,
where a wildly enthusiastic crowd welcomed him as the hero who
had unified the German-speaking people.

The extraordinary reception in Linz and
Vienna caused Hitler to change his plan. He now realized the
Austrians would not demand the status of a relatively independent
protectorate of Germany he had planned for them. The enthusiastic
welcome convinced him that Austria would readily accept, indeed
would welcome, total annexation. For it seemed as if everyone,
from the modest shopkeepers to the most elevated members of the
academic community, now embraced Hitler. In a shocking move, even
Theodor Cardinal Innitzer, the influential Archbischop of Vienna,
welcomed Hitler and ordered all the Catholic churches in the city
to fly the Nazi flag and to ring the church bells in honor of
Hitler's arrival in Vienna. As the Cardinal personally greeted
Hitler, he assured him of his own loyalty and that of all
Austrian Catholics - which was most of the population of Austria.
The Cardinal promised Hitler that Austria's Catholics would
become "the truest sons of the great Reich into whose arms they
had been brought back on this momentous day," provided that the
liberties of the Church were respected and its role in the
education of the young guaranteed.

That night, and for days on end, all hell
broke loose. Viennese mobs erupted in nationalistic fervor,
expressed by beating up Jews and destroying their property.
Foreign commentators, long accustomed to Nazi tactics in Germany,
were astonished by the wanton brutality of the Austrian Nazis,
and even German Nazis were amazed and emboldened by the
viciousness of the attacks in Vienna.

In his autobiography the German playwright
Carl Zuckmayer, who had moved to Austria in 1936 to escape
Hitler, described Vienna during the days following the annexation
of Austria as a city transformed "into a nightmare painting of
Hieronymus Bosch." It was as if:

... "Hades had opened its gates and vomited forth the basest,
most despicable, most horrible demons. In the course of my life
I had seen something of untrammeled human insights of horror or
panic. I had taken part in a dozen battles in the First World
War, had experienced barrages, gassings, going over the top. I
had witnessed the turmoil of the post-war era, the crushing
uprisings, street battles, meeting hall brawls. I was present
among the bystanders during the Hitler Putsch in 1923 in
Munich. I saw the early period of Nazi rule in Berlin. But none
of this was comparable to those days in Vienna. What was
unleashed upon Vienna had nothing to do with seizure of power
in Germany ... What was unleashed upon Vienna was a torrent of
envy, jealousy, bitterness, blind, malignant craving for
revenge. All better instincts were silenced ... only the torpid
masses had been unchained ... It was the witch's Sabbath of the
mob. All that makes for human dignity was buried."

Having watched the build-up of anti-Jewish
laws in Germany following Hitler's rise to power in 1933, my
parents did not need much convincing to realize that the violence
at the time of the annexation was not likely to fade away. We
knew that we had to leave - and to leave as soon as possible. My
mother's brother, Berman Zimels, had emigrated a decade earlier
to New York and established himself as an accountant. He provided
us expeditiously with affidavits that assured he would support us
upon our arrival in the United States. Even with these affidavits
it took about a year for my parents' Polish quota number to be
called. When our number finally was called, we had to emigrate in
stages because of United States immigration laws. My mother's
parents left first in February 1939, my brother and I next in
April 1939, and finally my parents in September 1939, only days
before World War II broke out.

During the one year that we lived under
Nazi rule, we experienced directly Vienna's humiliating form of
anti-Semitism. The day after Hitler marched into Vienna, every
one of my non-Jewish classmates - the entire class with the
exception of one girl - stopped talking and interacting with me.
In the park where I played I was taunted and roughed up. This
viciousness toward Jews, of which my treatment was a mild
example, culminated in the horrors of Kristallnacht, November 8,
1938. On the morning of November 7, 1938, a 17 year-old Jewish
youth, who was distraught over his parent's tragic fate at the
hands of the Nazis, shot a third secretary in the German Embassy
in Paris, mistaking him for the German Ambassador. In retaliation
for this single act, almost every synagogue in Germany and
Austria was set on fire. Of all the cities under Nazi control,
the destructiveness in Vienna on Kristallnacht was particularly
wanton. Jews were taunted and brutally beaten, expelled from
their businesses, and temporarily evicted from their homes so
that both could be looted by their neighbors. My father was
rounded up by the police together with hundreds of other Jewish
men. He was released a few days later only because he had fought
in the Austria-Hungarian army as a soldier in World War I. I
remember Kristallnacht even today, more than 60 years later,
almost as if it were yesterday. It fell two days after my ninth
birthday, on which I was showered with toys from my father's
shop. When we returned to our apartment a week or so after having
been evicted, everything of value was gone, including my
toys.

My last year in Vienna was, in a way, a
defining year, and it fostered the profound sense of gratitude I
came to feel for the life I have led in the United States. It is
probably futile, even for someone trained in psychoanalytic
thinking as I am, to attempt to trace the complex interests and
actions of my later life to a few selected experiences of my
youth. Nevertheless I cannot help but think that the experiences
of my last year in Vienna helped to determine my later interests
in the mind, in how people behave, the unpredictability of
motivation, and the persistence of memory. Over the years I have
returned to these subjects repeatedly as my professional
interests evolved from a youthful interest in European
intellectual history at Harvard, where I studied the motivation
of German intellectuals during the Nazi era, to an interest in
psychoanalysis with its more systematic approach to mental
processes, and finally to my interests in the biology of
conscious and unconscious memory.

My early experiences in Vienna almost
certainly contributed to my curiosity about the contradictions
and complexities of human behavior. How are we to understand the
sudden release of such great viciousness in so many people? How
could a highly educated and cultured society, a society that at
one historical moment nourished the music of Haydn, Mozart, and
Beethoven, in the next historical moment sink into barbarism?

Clearly the answer to this question is
complex, and many scholars of this period have attempted partial
answers. One conclusion, troubling to an academic like myself, is
that a society's culture is not a reliable indicator of its
respect for human life. This rather simplistic conclusion, of
course, raises the question: How can values within a society
become so radically dissociated? As far as I can tell, the
Viennese achieved this dissociation by shifting their frame of
reference. By defining Jews in racial rather than religious
terms, they were able to exclude Jews from the "more highly
evolved European Aryan race," the race they believed to be
responsible for the rise of Western civilization.

My last year in Vienna was likely also an
important factor in my more specific later interest in the
mechanisms of memory. I am struck, as others have been, at how
deeply these traumatic events of my childhood became burned into
memory - and I would emphasize that my experiences were trivial
compared to those of so many who were seriously harmed or killed.
For me, the frightening experiences of my last year in Vienna are
certainly the most powerful of my "flashbulb memories," the
emotionally charged and vivid memory of significant events that
came to fascinate me.

Resettlement in the United
States
Needless to say, arriving in the United States in April of 1939
was like a breath of fresh air. I never actually said "free at
last," but I felt it then and have ever since. We settled in
Brooklyn and lived at first with my mother's parents. My
grandfather Hersch Zimels was a religious and scholarly man who
was somewhat unworldly. My brother said that my grandfather was
the only man he knew who could speak seven languages but could
not make himself understood in any one of them. My grandfather
and I liked each other a great deal, and he readily convinced me
that he should tutor me in Hebrew during the summer of 1939 so
that I might be eligible for a scholarship at the Yeshiva of
Flatbush, an excellent Hebrew parochial school that offered both
secular and religious studies at a very high level. With his
tutelage I entered the Yeshiva in the fall of 1939. By the time I
graduated in 1944 I spoke Hebrew almost as well as English, had
read through the five books of Moses, the books of Kings, the
Prophets and the Judges in Hebrew, and also learned a smattering
of the Talmud.

After my parents arrived, my father worked
in a toothbrush factory. Even though he was not fond of working
in this factory, he threw himself into the work with his usual
energy and was soon reprimanded by the union steward for
producing toothbrushes too quickly and making other workers
appear slow. My father was undeterred. He simply loved America -
he often referred to it as the "goldene Medina," the golden
state. Even while still in Vienna he had read avidly the novels
of Karl May, an author whose books celebrated the conquest of the
American West and the bravery of the American Indians.

With time my father managed to save enough
money to rent and outfit a modest clothing store at 411 Church
Avenue in Brooklyn. We lived in an apartment above the store. My
father and mother worked together and sold simple women's dresses
and aprons, and men's shirts, ties, underwear, and pajamas. In
this way my parents earned enough not only to support us all but
also to send me to college and medical school. My father worked
in that store until the week before he died at age 78 in 1976. My
mother sold the store soon thereafter and died in 1991 at age
94.

Erasmus Hall High School and Harvard
College
In 1944, when I graduated from the Yeshiva of Flatbush elementary
school, it did not as yet have a high school. I went instead to
Erasmus Hall High School, a local public high school in Brooklyn
that was then academically very strong. Here I became interested
in history, in writing, and in girls. I worked on the school
newspaper and became sports editor. I also played soccer and was
co-captain of the track team. At the urging of one of my history
teachers, John Campagna, a Harvard alumnus, I applied to Harvard
College and was one of two students out of my class of about
1,400 to be admitted, both of us on scholarships! Fair Harvard
indeed!

Even though I was thrilled by my good
fortune, I was apprehensive about leaving Erasmus, convinced that
I would never again feel the sheer joy I had experienced there.
It was at Erasmus that I first sensed myself emerging from behind
the shadow of my brother Lewis. I now had distinctive interests
of my own - jazz music, sports, American constitutional history -
things that did not interest Lewis. At Harvard I majored in 19th
and 20th century European history and literature and wrote my
honors dissertation on The Attitude Toward National Socialism
of Three German Writers: Carl Zuckmayer, Hans Carossa, and Ernst
Junger. Each of these writers was then still alive and
represented a different position on the political spectrum of
fascism - uncompromising liberal opposition and emigration
(Zuckmayer), resigned acceptance and internal (spiritual)
emigration (Carossa), and intellectual support (Junger). I came
to the rather depressing conclusion that many German artists,
intellectuals, and academics succumbed all too eagerly and
opportunistically to the nationalistic fervor and racist
propaganda of National Socialism. Historical studies have found
that Hitler did not have widespread popular support in his first
year in office. Had intellectuals mobilized effectively and
brought along segments of the general population, Hitler's
government might well have been toppled.

I originally thought of doing graduate work
in European intellectual history, along the lines of my
undergraduate dissertation. However, in the course of my studies
at Harvard I befriended a fellow student, Anna Kris, who had also
emigrated from Vienna with her parents, Ernst and Marianne Kris,
both prominent psychoanalysts from Freud's circle. Anna and her
parents were very influential in getting me interested in
psychoanalysis. It is difficult to recapture now the
extraordinary fascination that psychoanalysis held for young
people in 1950. During the first half of the 20th century
psychoanalysis provided a remarkable set of insights into the
mind - insights about unconscious mental processes, psychic
determinism, and perhaps most interesting, the irrationality of
human motivation. As a result, in 1950, psychoanalysis outlined
by far the most coherent, interesting, and nuanced view of the
human mind than did any other school of psychology. In addition,
Anna's parents, who represented academic psychoanalysis in its
most intellectual and interesting form, were extraordinary people
- intelligent, cultured, and filled with enthusiasm. Ernst Kris,
a former curator of applied art at the Kunsthistorisches Museum
in Vienna, had been a world class art historian before becoming a
psychoanalyst. After taking up psychoanalysis, he focused on the
psychology of art, an area in which he helped train among others
the great historian Ernst Gombrich. Marianne Kris, a wonderful
therapist, was the daughter of Oskar Rie, a well-known Viennese
pediatrician and Freud's best friend. Marianne in turn was a
close friend of Freud's distinguished daughter, Anna Freud.

Both Ernst and Marianne Kris were extremely
generous and encouraging to me, as they were to Anna's other
friends. As a result of my frequent interactions with them and
their colleagues, I was converted to their view that
psychoanalysis offered a fascinating new approach, perhaps the
only approach, to understanding the mind, including the
irrational nature of motivation and unconscious and conscious
memory. With time this began to seem much more exciting and
interesting to me than European literature and intellectual
history.

Medical School at N.Y.U.
To become a practicing psychoanalyst, however, it was best to go
to medical school, become a physician, and train as a
psychiatrist - a course of study I had not previously considered.
So in 1951, almost impulsively, I went to summer school at
Harvard and took the required course in introductory chemistry.
That summer in Cambridge I shared a house with Robert Goldberger,
Henry Nunberg, James Schwartz, and Robert Spitzer, and we all
became lifelong friends. A few months later, based on this one
chemistry course and my overall college record, I was accepted at
N.Y.U. Medical School, with the proviso that I
complete the remaining course requirements before I entered
medical school in the fall of 1952.

I entered N.Y.U. Medical School dedicated
to studying psychiatry and becoming a psychoanalyst. Although I
stayed with this career plan through my internship and
psychiatric residency, by my senior year in medical school I had
become so interested in the biological basis of medical practice
(as had everyone else in my class) that I decided I had to learn
something about the biology of the mind. In the 1950s most
psychoanalysts thought of the mind in nonbiological terms.
However, several psychoanalysts - particularly two that I got to
know personally and who had a background in neurology, Lawrence
Kubie and Mortimer Ostow - had begun to discuss the potential
importance of the biology of the brain for the future of
psychoanalysis. After considerable discussion with them and with
another biologically oriented psychoanalyst, Sydney Margolin, I
decided to take an elective period at Columbia University with
Harry Grundfest. At that time N.Y.U. had no one on the faculty
who was doing basic neural science, and in 1955, Grundfest was
the most intellectually interesting neurobiologist in the New
York area.

Harry Grundfest's laboratory at Columbia
University
Grundfest had obtained his Ph.D. in zoology and physiology at
Columbia
in 1930 and went on to a post-doctoral fellowship at Columbia,
studying with Selig Hecht, an outstanding psychophysicist
interested in phototransduction - the transformation of light
into neural signals. (Hecht also was the teacher of George Wald, who won
the Nobel Prize in 1967 for discovering the chemical structure of
the visual pigments.) Grundfest then joined the Rockefeller
Institute in 1935, where he remained for a decade collaborating
with Herbert
Gasser. In 1944, while Grundfest was in his lab, Gasser
shared the Nobel Prize in Physiology or Medicine with Joseph Erlanger for
introducing the oscilloscope to neurophysiological studies. This
methodology allowed accurate temporal resolution of the waveform
and conduction velocities of the propagated action potential. In
collaboration with Grundfest, Gasser elaborated on his discovery
that the conduction velocity of the action potential is a
function of the diameter of the axon. Grundfest also carried out
reconstructions of the compound action potential from
cross-sectional measurements of axonal diameters in mixed nerves,
work that formed much of Gasser's Nobel
Prize Lecture.

In my decision to work with Grundfest, I
was strongly encouraged by a new friend, Denise Bystryn, an
extremely attractive and interesting French woman I had just met
and would later marry. Denise is also Jewish. Her mother helped
her father escape from a French concentration camp, and her
parents survived the war by hiding from the Nazis in the
southwest of France. During a good part of that time Denise was
separated from her parents, hidden in a Catholic convent near
Cahors. Denise's experiences, although more difficult, paralleled
mine in a number of ways that seemed significant to her but did
not seem at all important to me when we first met. However, over
the years, our shared experiences in Europe proved to be defining
in both our lives.

In 1949, Denise, her brother Jean-Claude,
and her parents emigrated to the United States. Denise attended
the Lycée Français de New York for one year and was
admitted at age 17 to Bryn Mawr College as a junior. On
graduating from Bryn Mawr at age 19, she enrolled at Columbia
University as a graduate student in sociology. When we met she
had just started research for her Ph.D. thesis in medical
sociology with Robert Merton. Denise's father, a gifted
mechanical engineer who unfortunately died one year before I met
Denise, had advised her to marry a poor intellectual because he
would likely be sufficiently ambitious to do interesting
scholarship. Denise believed she was following that advice (she
certainly married someone who was poor) and always encouraged me
to make decisions that favored my doing science.

In Grundfest's lab I spent the first
several months working on a number of projects with Dominick
Purpura, an independent young scientist just starting out on his
own career of cortical physiology. To my surprise I found my
first experience in a lab really interesting, and very different
from the classroom. Of course the research questions we were
asking fascinated me and the discussions were penetrating and
enjoyable. Dominick was very bright and very entertaining. (I
have referred to him as the Woody Allen of neurobiology.) But the
actual performance of the experiments was also pleasurable and,
when successful, very satisfying. Nevertheless, I began to worry
about the methods we were using to address rather sophisticated
questions about the electrical properties of dendrites. We were
using evoked responses that were initiated by stimulating small
areas of cortex, thereby activating thousands of neurons, and I
thought these methods were too indirect to give easily
interpretable results. Grundfest and Purpura, of course, were
also concerned and talked repeatedly about doing direct
intracellular recordings from cortical neurons, but neither
thought this was likely to succeed.

An introduction to Stephen
Kuffler
It was in this frame of mind that I was introduced to Stephen
Kuffler, a Viennese trained physician turned physiologist, who
(together with Bernard Katz and
John Eccles)
was to become one of my great neurobiological heroes. One evening
Grundfest threw into my lap the September 20, 1955 issue of the
Journal of General Physiology, with three of Kuffler's
papers on excitation and inhibition in the dendrites and soma of
isolated sensory nerve cells of the lobster and crayfish.
Grundfest said something about Kuffler's being very good, and
that these papers provided direct evidence for the graded
properties of dendrites evidence that was consistent with what he
and Purpura were seeing in cortica; neurons. I took the issue
home and read the papers as best I could. Although I understood
relatively little, one thing stood out immediately. Kuffler was
studying the dendrites in a preparation in which he actually saw
the dendrites and could record from them directly. For studying
dendrites Kuffler used an invertebrate sensory neuron that sent
its dendrites into skeletal muscle much like the muscle spindles
of vertebrates. In the introduction to the three papers Kuffler
wrote:

"The greatest advantage of the present
preparation lies in its accessibility, since all cellular
components can be isolated and visually observed. Further, the
state of excitability of the structures could be controlled and
graded by utilizing the physiological mechanisms given by the
stretch receptor nature of the preparation...

It seems of special interest that the
sensory cell of crustacea possessed numerous anatomical
features, which bear a striking resemblance to many central
nervous system cells of vertebrates."

I learned from Kuffler's papers a new
criterion for how good science is done - the importance of having
a preparation suitable to testing the questions to be answered.
Kuffler taught me to respect the power of invertebrate
neurobiology.

On graduating from medical school in June
1956, I married Denise and, after a brief honeymoon in
Tanglewood, I started an internship at Montefiore Hospital as she
continued her thesis research at Columbia. I returned to
Grundfest's lab, spending six weeks with Stanley Crain, who had
pioneered the electrophysiological study of nerve cells in tissue
culture. Stanley taught me how to make microelectrodes and how to
obtain and interpret intracellular recordings from the crayfish
giant axon. These experiments confirmed the insights I had gained
from reading Kuffler's paper. From Stanley I also received my
first insights into the universality of cellular processes.

Based on my two brief periods in his
laboratory, Grundfest offered to nominate me for a position at
the NIH, an
alternative to serving in the physician's draft, which provided
medical personnel for the military during the years following the
Korean War. On the basis of Grundfest's recommendation, I was
accepted by Wade Marshall, Chief of the Laboratory of
Neurophysiology at NIMH/NINCDS.

The laboratory of neurophysiology at the
National Institutes of Health
By the time I arrived in Bethesda, Wade Marshall had passed the
peak of what had been a remarkable career. In the 1930s he was
arguably the most promising and accomplished young scientist
working on the brain in the United States. As a graduate student
at the University of Chicago in Ralph Gerard's lab in 1936,
he discovered that one could record electrical deflections in the
somatosensory processing area of the cerebral cortex by moving
the hairs of a cat's limb. He appreciated that one might use this
electrical signal (the evoked response) to map the representation
of the body surface on the brain.

To study this further, he joined Phillip
Bard, Chairman of the Department of Physiology at the Johns Hopkins
Medical School, as a post-doctoral fellow. In 1937, Bard had
already established himself as a major presence in American
neurophysiology. Together with his student Clinton Woolsey, Bard
had surgically removed the somatic sensory cortex of the monkey
and studied its effect on the "placing reaction," a form of
tactile behavior. Marshall joined up with Woolsey and Bard and
together they carried out a classic series of studies in which
they mapped sensory inputs from the body surface in the somatic
sensory cortex and showed that a topographical representation of
the entire body is wired into the brain. This provided the first
systematic view of the neural representation in the brain of a
sensory system. Today, this map is still shown in every textbook
of neural science. Marshall next collaborated with John Talbott
and mapped the retinal inputs in the striate cortex. Finally,
with Harlow W. Ades, he mapped the cochlear inputs in the
auditory cortex.

With these classic studies Marshall
revolutionized the study of the sensory representations in the
brain and showed that the brain had systematic topographical maps
of the sensory surface for each of the three major sensations -
touch, vision, and hearing. These marvelous scientific
achievements came at a price, however, leaving Marshall so
psychologically fatigued that he collapsed and, for a number of
years, left science altogether. When he returned, in about 1945,
he moved on to a completely new problem: the study of spreading
cortical depression, a propagating, reversible silencing of
cortical electrical activity. Marshall enjoyed doing occasional
experiments, but he had lost his scientific drive and now focused
much of his energy and interests on administrative matters, which
he did well. Although eccentric, moody, and somewhat
unpredictable, he was a wonderful lab chief. In particular, he
was supportive and generous to young scientists and gave us a
great deal of freedom.

Just before I arrived at NIH in 1957, the
neurosurgeon William Scoville and the cognitive psychologist
Brenda Milner had described the now-famous patient H.M. In order
to treat intractable bilateral temporal lobe epilepsy, Scoville
had removed on both sides of H.M.'s brain the medial temporal
lobes, including a structure deep to them called the hippocampus.
As a result of this procedure, H.M.'s seizures were largely
eliminated. But, while retaining all cognitive functions, H.M.
lost the ability to put new information into long-term memory.
These findings pinpointed the medial temporal lobe and the
hippocampus as sites specialized for memory storage.

Until the Scoville and Milner paper, the
person most identified with attempts to localize memory was Karl
Lashley, Professor of Psychology at Harvard and perhaps
the dominant figure in American neuropsychology in the first half
of the 20th century. Lashley explored the surface of the cerebral
cortex in the rat, and systematically removed different cortical
areas. In so doing, he failed to identify any particular brain
region that was special to or necessary for the storage of
memory. Based on these experiments, Lashley formulated the law of
mass action, according to which memory is not localized to any
specific region of the cortex but was a distributed property of
the cortex as a whole. The extent of any memory defect, Lashley
argued, was correlated with the size of the cortical area
removed, not with its specific location.

Since I had already begun to think about
problems in psychiatry and psychoanalysis in biological terms,
the cell and molecular mechanisms of learning and memory struck
me as a wonderful problem to study. I had first become interested
in the study of learning at Harvard, where B.F. Skinner, the
great behaviorist, was a dominant force in the 1950s. It was
clear to me even then that learning and memory were central to
behavior, and thus to psychopathology and to psychotherapy.
Nothing was known about the cellular mechanisms of learning and
memory, and now the cellular techniques for studying them were
just becoming available - some beginnings of which I had learned
from Stanley Crain in Grundfest's lab.

My initial ideas about how to tackle the
biology of memory upon arrival at the NIH were confused and
vague. Because intracellular recordings seemed to me such a
powerful analytic tool for studying nerve cells, and because the
hippocampus seemed particularly important for memory, I wanted to
explore the hippocampus in cellular terms. This was made even
more attractive for me because, as the great Spanish anatomists
Ramón y
Cajal and Lorente de Nó had pointed out, the cellular
architecture of the hippocampus is remarkably conserved among
mammals, and the main cell type, the pyramidal cell, is found in
a discrete layer that is easy to target with microelectrodes. In
addition, the pyramidal cells send their axons into a large fiber
tract (the fornix), which allows the pyramidal cells to be
identified electrophysiologically by stimulating the axons in the
fornix and backfiring the pyramidal cells. I thought it would be
interesting to compare the pyramidal neurons to the only other
mammalian neurons that had been well studied at that time - the
motor neurons of the spinal cord. I had the idea that the
properties of the pyramidal cells themselves might reveal
something about memory storage. I was emboldened to try this
technically demanding study because Karl Frank was in the
laboratory next to ours, pioneering the examination of spinal
motor neurons with intracellular recordings in parallel with John
Eccles. Although Frank himself thought that studying the
hippocampus was chancy, he was not discouraging.

Almost as soon as I began, my research took
an extremely fortunate turn in the person of Alden Spencer, who
arrived in Marshall's lab having just graduated from the University of Oregon
Medical School. Like me, Alden was becoming interested in the
biology of learning and memory. It therefore took little effort
for me to convince him that we should join forces on the
hippocampus. Although Alden had no experience with intracellular
recordings, he had done electrophysiological research on the
brain at the University of Oregon Medical School, where he worked
with John Brookhardt. Among Alden's many remarkable talents, he
had good surgical skills and a fine knowledge of the anatomical
organization of the mammalian brain.

Being both naïve and brash, we were
not reluctant to tackle what appeared to Frank and others to be
technically difficult problems, namely obtaining intracellular
recordings from cortical neurons in a pulsating brain. Alden and
I developed a simple way of reducing pulsations in the
hippocampus that allowed us to obtain, on occasion, high-quality
recordings for a long enough period - up to one hour - to carry
out an initial analysis of the electrical properties of the
hippocampal pyramidal cells. By applying to the hippocampus the
powerful methodologies we learned from Frank, we easily picked
some low-lying intellectual fruit. First, we found that action
potentials in hippocampal neurons were initiated not only at the
axon hillock, as in motor neurons, but also at a second site,
which we inferred to be the apical dendrites. These putative
dendritic action potentials, which we called fast prepotentials,
appeared to trigger the firing at the axon hillock. Second, we
found that the hippocampal neurons, unlike motor neurons, were
not silent in the absence of synaptic activity, but tended to
fire spontaneously, and that this firing often took the form of
bursts of spikes that were maintained by summation of
depolarizing afterpotentials. Third, we found that the
hippocampal neurons engaged a powerful recurrent inhibitory
system that gave rise to a prolonged inhibition - several orders
of magnitude longer than the inhibition seen in the spinal
cord.

The mere technical success of obtaining
intracellular recordings from hippocampal neurons, and the few
interesting questions we were able to address, caught the
enthusiastic attention of, and drew encouragement and help from,
our senior colleagues at the NIH - Marshall, Frank, Michael
Fuortes, Frank's gifted colleague and the great Japanese-American
biophysicist Ichiji Tasaki. When John Eccles visited the NIH, he
also was generous in his comments. But even in our brashest
moments, we both realized that ours was a typical NIH story. In
the Intramural Program at the NIH, young inexperienced people
were given the opportunity to try things on their own, knowing
that wherever they turned there were experienced people to help
out.

Moreover, as Alden and I reviewed our work
we realized that the cellular properties of hippocampal neurons
were not sufficiently different from those of spinal neurons to
explain the ability of the hippocampus to store memory. Thus, it
dawned on us what in retrospect is quite obvious: that the
neuronal mechanisms of learning and memory probably did not
reside in the properties of the neurons themselves. Rather,
because the signaling properties of neurons are quite alike, we
began to think that what must matter is how neurons are
functionally connected. The basis of learning must reside in the
modification of interconnections by appropriate sensory signals.
This conclusion, so clear in retrospect, emerged only gradually
as we learned, mostly through reading and discussions with one
another, to think more effectively about the biology of learning
and memory.

This realization led us to reappraise our
strategy. Since the hippocampus has a large number of neurons and
an immense number of interconnections, it was not the place to
begin. Even though we were now quite familiar with the
hippocampus, it would be extremely difficult to work out how
sensory information specific to learning reached the hippocampus
or how learned information processed by the hippocampus might
influence motor output.

Alden and I therefore became convinced that
to make headway with the study of learning at the cellular level
required a very different approach. Alden, a committed mammalian
neurophysiologist, turned to the study of the spinal cord,
particularly the modifiability of spinal reflexes, and went on to
make important contributions in collaboration with Richard
Thompson.

However, even the spinal cord proved too
difficult for a detailed cellular analysis, and both Alden and
Thompson ended up leaving it.

The search for a tractable system for
studying learning
Influenced by Kuffler, Grundfest, and Crain, I yearned for a more
radically reductionist approach to the biology of learning and
memory. I wanted a system that would serve the cellular study of
learning as well as the squid giant axon had served for studies
of the action potential, or the nerve-muscle synapse of the frog
had served for the study of synaptic transmission. I wanted to
examine learning in an experimental animal in which a simple
behavior was modifiable by learning. Ideally that behavior should
be controlled by only a small number of large and accessible
nerve cells, so that the animal's overt behavior could be related
to events occurring in the cells that control that behavior.

Such a reductionist approach has been
traditional in biology. In neurobiology it is exemplified by the
work on the squid giant axon by Hodgkin and Huxley, the
nerve-muscle synapse of the frog by Bernard Katz, and the eye of
Limulus by Keefer Hartline. When
it came to the study of behavior, however, most investigators
were reluctant to apply a strict reductionist strategy. In the
1950s and 1960s it was often said that behavior was the area in
biology in which simple animal models, particularly invertebrate
ones, were least likely to produce fruitful results because the
brain that really learns, the mammalian brain, especially the
human brain, is so complex that inferences from studies of
invertebrates would not stand up. It was thought that humans,
because of higher-order capabilities not found in simpler
animals, must have types of neuronal organization that are
qualitatively different from those found in invertebrates.
Although these arguments held some truth, they overlooked certain
critical issues. Work by students of comparative behavior, such
as Konrad
Lorenz, Niko
Tinbergen, and Karl von Frisch, had
already shown that certain behavior patterns, including
elementary forms of learning, were common to humans and simple
animals. From the outset I therefore believed that the mechanisms
of memory storage were likely to be conserved in phylogeny, and
that a cellular analysis of learning in a simple animal would
reveal universal mechanisms that are also employed in more
complex organisms.

Not surprisingly, I was strongly
discouraged in the early days from pursuing this strategy by some
senior researchers in neurobiology, particularly John Eccles. His
concern reflected, in part, the existing hierarchy of acceptable
research questions in neurobiology. Few self-respecting
neurophysiologists, I was told, would leave the study of learning
in mammals to work on an invertebrate. Was I compromising my
career? Of an even greater concern to me were the doubts
expressed by some very knowledgeable psychologists I knew, who
were sincerely skeptical that anything interesting about learning
and memory could be found in a simple invertebrate animal. I had
made up my mind, however. Since we knew nothing about the cell
biology of learning and memory, I believed that any insight into
the modification of behavior by experience, no matter how simple
the animal or the task, would prove to be highly informative.

After an extensive search that included
crayfish, lobster, flies, and the nematode worm Ascaris, I
settled on Aplysia, the giant marine snail. Aplysia
offered three major technical advantages: (1) its nervous system
has a small number of cells, (2) the cells are unusually large,
and, as I realized with time, (3) many of the cells are invariant
and identifiable as unique individuals. Before leaving the NIH in
1960, I arranged with Ladislav Tauc, one of the two people in the
world then working on Aplysia, to join him in September
1962, as a postdoctoral fellow, as soon as I had completed my
residency training. Here again, Denise's advice was decisive. The
only two people working on Aplysia were French - Tauc's
lab was in Paris, and Angelique Arvanitaki-Chalazonitis worked in
Marseilles. So far so good! But, Denise, ever the Parisian
chauvinist, thought that living in Marseilles would be like
living in Albany (a small town in upstate New York). So Tauc and
Paris it was, and that proved an excellent choice.

Residency training in psychiatry at the
Harvard Medical School
However, before I would leave for Paris I had already committed
to a two-year residency training in psychiatry. I therefore left
the NIH in the spring of 1960 to start my psychiatric residency
at the Massachusetts Mental Health Center of the Harvard Medical
School. When I arrived at Harvard, I found an unanticipated
bonus. Steven Kuffler, whose thinking had so influenced my own,
had been recruited one year earlier from Johns Hopkins to build
up neurophysiology at Harvard. Kuffler brought with him several
young post-doctoral fellows - David Hubel, Torsten Wiesel, Ed
Furshpan, and David Potter - each of whom was extraordinarily
gifted. In this way Kuffler succeeded, in one fell swoop, in
setting up at Harvard the premier group of neural scientists in
the country. I now had my first opportunity to interact with
Kuffler and with the remarkable people he had assembled around
him. Even though I was in fulltime residency training, Kuffler
and his group were extremely accessible, and their generosity
allowed me to remain intellectually engaged in neurobiology.
Moreover, Jack Ewalt, the Professor of Psychiatry at the
Massachusetts Mental Health Center, provided me with funds and
space so that I even managed to do some research in my spare
time. I obtained the first intracellular recording from
hypothalamic neuro-endocrine cells and found that these
hormone-releasing cells had all the electrical properties of
normal nerve cells.

During my psychiatric residency I began to
think about simple forms of learning in preparation for work on
Aplysia. I read Kimble's wonderful revision of Hilgard and
Marquis's classical text Conditioning and Learning, and I
reread Skinner's great book The Behavior of Organisms.
This reading made me realize that the paradigms of simple
learning articulated by Pavlov and Thorndyke,
describing changes in behavior in response to controlled
stimulation, included precise protocols for stimulating
experimental animals. It occurred to me that the paradigms they
described - habituation, sensitization, classical conditioning,
and operant conditioning - could readily be adapted to
experiments with an isolated Aplysia ganglion using
artificial electrical rather than natural sensory stimuli. While
recording the behavior of a single cell in a ganglion, one nerve
axon pathway to the ganglion could be stimulated weakly
electrically as a conditioned stimulus, while another pathway was
stimulated as an unconditioned stimulus, following the exact
protocol used for classical conditioning with natural stimuli in
intact animals. One could then see whether synapses changed
systematically in response to these patterns of stimulation, and,
if so, whether the synaptic changes in any way paralleled changes
in the overt behavior of intact animals, which classical
psychologists had described. It thus dawned on me that in this
way one could begin to take an initial step toward the study of
learning in the intact animal by analyzing what I soon began to
call analogs of learning - higher-order stimulus sequences
based on patterns of stimulation used in learning experiments in
intact behaving organisms, but applied directly to a neuronal
system.

Paris, Aplysia, and neural analogs of
learning: chemical synapses prove to be remarkably
plastic
Based on this idea, I wrote a successful application for an
NINCDS postdoctoral fellowship for work to be done in Tauc's
laboratory. And in September 1962, about a year after our son
Paul was born, the three of us took off for Paris. Tauc proved an
excellent person to work with; both our interests and our areas
of competence complemented each other. He was, of course,
completely at home with Aplysia, but he also had a strong
background in physics and biophysics, which I lacked. Born in
Czechoslovakia, Tauc had originally studied the electrical
properties of plant cells. As a result, he had no experience with
behavior and had up to this point thought little about the
problems of neuronal integration that dominated thinking about
the mammalian brain - problems that Alden and I had discussed
incessantly. Tauc was quite enthusiastic about my approach, which
proved even more effective than anticipated. In my cellular
studies of analogs of habituation, sensitization, and classical
conditioning in Aplysia, I found synaptic changes that
paralleled the behavioral changes seen in experiments on intact
animals. This encouraged us to write in our 1965 paper in the
British Journal of Physiology:

"The fact that the EPSPs (excitatory postsynaptic
potentials) can be facilitated for over half-an-hour with an
input pattern scheme designed to simulate a behavioral
conditioning paradigm, also suggests that the concomitant
changes in the efficacy of synaptic transmission may underlie
certain simple forms of information storage in the intact
animal."

A brief return to the Harvard Medical
School
Upon completing a very productive 16-month stay in Tauc's
laboratory, I returned to Harvard in November 1963. More than a
year and a half later, in July of 1965, our daughter Minouche was
born, completing our family - one boy, one girl - exactly what we
had hoped for.

During this period I struggled with three
choices that were to have a profound effect on my subsequent
career. First, I realized that to do effective science I could
not combine basic research and a clinical practice in
psychoanalysis, as I had earlier hoped. I therefore decided not
to apply to the Boston Psychoanalytic Institute, a decision which
meant that I would not attempt to become a psychoanalyst but
devote myself full-time to science. It was my strong sense that
one of the problems within academic psychiatry, a problem that
has become only worse with time, is that young people take on
much more than they can handle effectively. I concluded that I
could not and would not do that.

The second choice arose a few months later
when Dr. Ewalt and Dr. Howard Hiatt, then chairmen of the
Department of Medicine at the Beth Israel Hospital at Harvard,
suggested that I take on the newly vacated chairmanship of the
Department of Psychiatry at the Beth Israel Hospital. For a
moment I was forced to rethink my decision to focus full time on
science. The person who had just left that position, Grete
Bibring, was a leading psychoanalyst who had been a colleague of
Marianne and Ernst Kris in Vienna. Earlier in my life achieving
this position would have represented my highest aspiration. But
by 1965, my thinking had moved in a very different direction, and
I decided against it with Denise's strong encouragement. (Denise
summarized it simply: 'What?" she said, "throw your scientific
career away?") Instead, I made my third decision. I decided to
leave Harvard and accept an invitation to start a small
neurophysiology group focused specifically on the neurobiology of
behavior in the Departments of Physiology and Psychiatry at the
New York University Medical School.

Harvard was quite wonderful, and it was not
easy to leave that intellectually heady neurobiology environment.
My interaction with Kuffler had increased after my return from
Paris and, until his death in 1980, Kuffler proved a marvelous
friend and counselor. Moreover, my interactions during this
period with members of Kuffler's group - Hubel, Wiesel, Furshpan,
Potter, and Ed Kravitz, a biochemist who joined them later - were
extensive and I learned much from them. Many years later, at a
small meeting at the Marine Biological Laboratory in Woods Hole
in honor of Steve Kuffler, I was surrounded by Steve's Harvard
entourage, some of whom were struggling with the decision of
whether to leave Harvard for attractive positions elsewhere. I
could not resist beginning my lecture with the remark, "I am here
as living proof that there is life after Harvard."

New York University and a focus on the
behavior of Aplysia
The position at N.Y.U. had several great attractions that, in the
long run, proved critical. First, it brought us back to New York
and closer to my parents and to Denise's mother, all of whom were
having medical problems that benefited from our being nearby.
Second, N.Y.U. gave me the opportunity to recruit an additional
senior neurophysiologist, and Alden Spencer agreed to move to
N.Y.U. from the University of Oregon Medical School where he had
returned after his stay at the NIH, and to occupy the laboratory
next to mine. Although Alden and I never collaborated
experimentally again, we talked daily not only about our science
- the neurobiology of behavior - but also about almost everything
else, until his untimely early death at age 46 from amyotrophic
lateral sclerosis in 1977, when we had already moved to Columbia
University. During the period he was alive, no one influenced my
thinking on matters of science as much as Alden. I still think
about him frequently.

Alden and I arrived at N.Y.U. together in
the winter of 1965. Within a year we were joined by a biochemist,
James H. Schwartz, whom I had first met in the summer of 1951 at
Harvard summer school and who was now a member of the Department
of Microbiology at N.Y.U. and was becoming interested in
behavior. The three of us formed the nucleus of the Division of
Neurobiology and Behavior at N.Y.U.

With several important decisions behind me,
I made a strong effort to focus on whole-animal behavior. In
France I had found that chemical synapses are remarkably plastic;
they could readily undergo long-lasting changes in strength. But
I had no evidence that these analogs of learning were in fact
behaviorally meaningful. I had no reason to believe that these
are the sorts of changes that actually occur when an animal
learns something. Although during my last few weeks in France I
had begun to replicate my results by substituting natural stimuli
for electrical stimulation of nerves, I still had not shown that
synaptic plasticity actually occurred during behavioral learning.
As a first step I thought it essential to show that
Aplysia was capable of learning. With this in mind, I set
about recruiting a postdoctoral fellow with a specific interest
in behavioral learning. I was fortunate to recruit, first to
Harvard and then to N.Y.U., Irving Kupfermann, an extremely
critical and thoughtful student of behavior. We were later joined
by another learning psychologist, Harold Pinsker, and together we
set about delineating a very simple behavior that we could study:
the gill-withdrawal reflex. We quickly found that this simple
reflex could readily be modified by two forms of learning:
habituation and sensitization.

As we explored the two forms of learning,
we focused on short-term memory. In 1971, we were joined by
another experienced behavioral psychologist, Tom Carew, who
brought a new level of energy and insight to our behavioral
studies. He arrived as Pinsker was leaving, and soon after we
shifted from working with restrained to unrestrained animals,
thus opening up the study of long-term memory. Tom found that
spaced repetition converted the memory for short-term habituation
and sensitization to longer-lasting memories. In 1981, after
several unsuccessful attempts, Carew, Terry Walters, Tom Abrams,
and Robert Hawkins finally were able to define the conditions for
reliably producing classical conditioning in Aplysia. This
was a particularly exciting period; Carew, Walters, Hawkins, and
I met regularly to discuss how to explore whether a simple
reflex, in a simple invertebrate, could show the higher-order
cognitive features of classical conditioning recently
demonstrated in mammals by Leo Kamin and somewhat later by Robert
Rescorla and Alan Wagner. Soon, Hawkins indeed was able to
demonstrate that the gill-withdrawal reflex can undergo
second-order conditioning, blocking, overshadowing and other
cognitive aspects of associative learning, features that were
surprising to uncover in such a simple behavior.

We thus were able to describe a rather rich
repertory of learning in Aplysia. But long before this
inventory of the animal's behavior was complete, we returned to
our initial concerns. What happens in the brain of an animal when
it actually learns a task? How does it remember? We proceeded,
first with Kupfermann and Vincent Castellucci and then with Jack
Byrne and Hawkins, to work out most of the neural circuit of the
gill-withdrawal reflex. We identified specific sensory neurons
and motor cells that produced movements of the gill. Next, we
found that the sensory neurons made direct connections to the
motor neurons as well as indirect connections through
interneurons, both excitatory and inhibitory. The aversive tail
stimuli that produced sensitization of the gill-withdrawal reflex
activated modulatory interneurons that acted on terminals of the
sensory neurons. We now could turn to think about how learning
might occur in this reflex.

Cellular mechanisms of
learning
At the end of the 19th century Ramón y Cajal introduced the
principle of connection specificity, according to which, during
development, a neuron will form connections only with certain
neurons and not with others. Kupfermann, Castellucci, and I saw
in the circuitry of the gill-withdrawal reflex of Aplysia
this remarkable regularity of connections that Cajal referred to
and we saw, in exquisite detail, that specific identified cells
made invariant connections to one another. But this invariant
organization of neurons posed deep questions. How could we
reconcile hardwired circuits in the nervous system and the
specificity of connections with the animal's capability for
learning? Once acquired, where or how is learned information
retained in the nervous system?

One solution was proposed by Ramón y
Cajal in his Croonian Lecture to the Royal Society of
London in 1894 when he suggested that "... mental exercise
facilitates a greater development of the protoplasmic apparatus
and of the nervous collaterals in the part of the brain in use.
In this way, pre-existing connections between groups of cells
could be reinforced by multiplication of the terminal branches of
protoplasmic appendices and nervous collaterals."

This remarkably prescient idea was by no
means generally accepted. On the contrary, different theories of
learning at various times held the attention of neural
scientists. Two decades after Ramón y Cajal's proposal, the
physiologist Alexander Forbes suggested that memory is sustained
not by changes in synaptic strength of the sort suggested by
Ramón y Cajal, but by dynamic changes resulting from
reverberating activity within a closed loop of self-exciting
neurons. This idea was elaborated by Ramón y Cajal's
student, Rafael Lorente de Nó, who found in his own and in
Ramón y Cajal's analyses of neural circuitry neurons that
were interconnected in closed pathways and could thereby sustain
reverberatory activity, thus providing a dynamic mechanism for
information storage. In his influential book The Organization
of Behavior (1949), D.O. Hebb proposed that a "coincident
activity" initiated the growth of new synaptic connections as
part of long-term memory storage. But for short-term memory, Hebb
invoked a reverberatory circuit:

"To account for permanence, some structural change seems
necessary, but structural growth presumably would require an
appreciable time. If some way can be found of supposing that a
reverberatory trace might cooperate with the structural change,
and carry the memory until the growth change is made, we should
be able to recognize the theoretical value of the trace, which
is an activity only without having to ascribe all memory to it.
The conception of a transient, unstable reverberatory trace is
therefore useful. It is possible to suppose also some more
permanent structural change reinforces it."

Similarly, in The Mammalian Cerebral
Cortex, an influential book of 1958, B. Deslisle Burns
challenged the relevance of synaptic plasticity to memory.

"The mechanisms of synaptic facilitation which have been
offered as candidates for an explanation of memory ... have
proven disappointing. Before any of them can be accepted as the
cellular changes accompanying conditioned reflex formation, one
would have to extend considerably the scale of time on which
they have been observed to operate. The persistent failure of
synaptic facilitation to explain memory makes one wonder
whether neurophysiologists have not been looking for the wrong
kind of mechanisms."

Indeed, some scholars even minimized the
importance of specific neuronal connections in the brain,
advocating instead mechanisms of learning that were partially or
even totally independent of "pre-established" conduction
pathways. This view was held by Wolfgang Kohler and the famous
Gestalt psychologists, and subsequently by the neurophysiologists
Ross Adey and Frank Morrell. Thus, in 1965, Adey wrote:

"No neuron in natural or artificial isolation from other
neurons has been shown capable of storing information in the
usual notion of memory. ... In particular, the possibility
exists that extraneuronal compartments may participate
importantly in the modulation of the wave process that
characterize the intracellular records, and that these wave
processes may rank at least equivalently with neuronal firing
in the transaction of information and even more importantly in
its deposition and recall."

Finally, there were memory macromolecular
notions advocated by Holger Hyden, based upon his finding of
changes in the nucleotide composition of RNA. He proposed that
learning gave rise to a specific pattern of instructional neural
activity that altered the stability of RNA molecules, so that one
base can exchange for another. In this way, new RNA molecules are
formed with new base sequences that are specific to the
instructing pattern of neural activity induced by learning.
Hyden's hypothesis thus implied that the patterns of stimulation
activated by learning could introduce changes in RNA.

We were now therefore in a position to test
experimentally which, if any, of these ideas had merit. Using the
gill-withdrawal reflex, we quickly established that memory in the
Aplysia nervous system is not represented in self-exciting
loops of neurons but in changes in synaptic strength. We found
that all three simple forms of learning - habituation,
sensitization, and classical conditioning - lead to changes in
the synaptic strength of specific sensory pathways, and that
these changes parallel the time course of the memory process.
These findings, which had been fully anticipated by our earlier
studies of analogs of learning, gave rise to one of the major
themes in our thinking about the molecular mechanisms of memory
storage. Even though the anatomical connections between neurons
develop according to a definite plan, the strength and
effectiveness of those connections is not fully determined
developmentally and can be altered by experience.

We therefore concluded the third of our
1970 series of consecutive papers in Science on the cellular
mechanisms of learning with the following comments:

"... the data indicate that habituation and dishabituation
(sensitization) both involve a change in the functional
effectiveness of previously existing excitatory connections.
Thus, at least in the simple cases, it seems unnecessary to
explain the behavioral modifications by invoking electrical and
chemical fields or a unique statistical distribution in a
neural aggregate. The capability for behavioral modification
seems to be built directly into the neural architecture of the
behavioral reflex.

Finally, these studies strengthen the assumption ... that a
prerequisite for studying behavioral modification is the
analysis of the wiring diagram underlying the behavior. We
have, indeed, found that once the wiring diagram of the
behavior is known, the analysis of its modification becomes
greatly simplified. Thus, although this analysis pertains to
only relatively simple and short-term behavioral modifications,
a similar approach may perhaps also be applied to more complex
as well as longer lasting learning processes."

A beginning molecular analysis of memory
storage
Having defined a critical site of plasticity, the situation
became ripe for a molecular analysis. Here again I could not have
been more fortunate. As I mentioned earlier, soon after I arrived
at N.Y.U. I ran into James Schwartz. Jimmy had attended N.Y.U.
Medical School two years behind me, but we had not really talked
since I left N.Y.U. in 1956. After medical school Jimmy obtained
a Ph.D. with Fritz Lipmann at the Rockefeller
University, studying enzyme mechanisms and protein
translation in cell-free bacteria extracts. As he and I began to
talk again, he mentioned that he was thinking of moving from
E. coli to the brain. Aplysia seemed ideal for
biochemical study of individual nerve cells, so in 1966, Schwartz
and I joined forces to carry out biochemical studies on
individual identified nerve cells of Aplysia.

Jimmy soon showed that each nerve cell in
Aplysia had a specific transmitter biochemistry. Cells
that we had presumed on pharmacological grounds to be cholinergic
did in fact synthesize and release acetylcholine. With time,
Jimmy became interested in the molecular mechanisms of synaptic
plasticity, and together we began to examine the role of protein
synthesis in memory storage. We knew from the work of Louis
Flexner and Bernard Agranoff in the mid 1960s that long-term
memory in vertebrates required protein synthesis whereas
short-term memory did not. In our first study together in 1971,
we found that blocking protein synthesis for 24 hours did not
prevent the short-term synaptic changes associated with
habituation and sensitization. That finding made us think that
short-term changes representing memory storage might involve
activation of a second-messenger pathway, for example, the cyclic
AMP (cAMP) cascade, whose actions might persist for periods
longer than the millisecond duration of conventional synaptic
actions.

In the discussion of our 1971 paper on the
role of protein synthesis and synaptic plasticity, we wrote:

"Alterations in molecular configuration would not be
expected to persist for long periods of time, although
molecular changes lasting for several minutes have been
observed. ... Most likely, the biochemical mechanisms
underlying these short-term plastic changes are composed of a
series of sequential reactions which result in a new
distribution of transmitter substance. Mechanisms involving
cyclic 3',5'AMP might serve as one example of a series of
reactions which result in transient enhancement in the activity
of a critical enzyme system. A pathway of this kind might
trigger the mobilization of transmitter from one component (a
long term store) to another (an immediately releasable
store).

... If our conclusion is correct, ... rapidly synthesized
RNA cannot immediately play a role in neuronal functions; it
might however, be important for long-term neuronal
processes."

Sutherland and Rall had already shown in
brain slices that several neurotransmitters known to exist in the
brain could increase the concentrations of cAMP by activating the
enzyme adenylyl cyclase that converted ATP to cAMP. We
appreciated that we had a particularly good experimental
preparation for examining, on the cellular level, the role of
second-messenger pathways in synaptic transmission, synaptic
plasticity, and memory storage. In 1972, Schwartz, Howard Cedar,
and I found that stimulation of the pathway involved in
sensitization increased the level of cAMP in the entire abdominal
ganglion. Schwartz and Cedar next found that the transmitter
serotonin could also increase cAMP, providing the initial
evidence that serotonin might activate an adenylyl cyclase in
Aplysia.

Columbia University and the molecular
analysis of short-term memory
It was at this time that I was invited to move from N.Y.U. to the
Columbia University College of
Physicians and Surgeons to become the founding director of
the Center for Neurobiology and Behavior. I was able to persuade
James Schwartz, Alden Spencer, and Irving Kupfermann (who was by
then an Associate Professor, having established an independent
research program concerned with feeding and motivational state in
Aplysia) to join me. This move was attractive to me for
several reasons. Historically, Columbia has had a strong
tradition in neurology and psychiatry, and a friend and former
clinical teacher, Lewis Rowland, was about to assume the
chairmanship of the Department of Neurology. In addition, I had
my first experience in neurobiology at Columbia with Harry
Grundfest who was now retiring and I was being recruited to
replace him. Finally, Denise was on the Columbia faculty and our
house in Riverdale was near Columbia, thereby greatly simplifying
our lives.

In 1974, just after arriving at Columbia,
Castellucci and I went back to the elementary circuit of the
gill-withdrawal reflex to determine the exact site of the
synaptic change produced by short-term sensitization. We wanted
to know which component of the synapse changes. Is it, as we
suspected, based on indirect evidence, the presynaptic element of
the synapse where chemical transmitter is released, or is it the
postsynaptic site which contains the receptors which bind and
respond to the transmitter? Using a quantal analysis, we found
that the synaptic facilitation characteristic of sensitization is
presynaptic and that inhibitors of serotonin block this
presynaptic facilitation. Later, Hawkins and I found that tail
stimuli that initiate sensitization activate a set of modulatory
interneurons, the most important of which are serotonergic. The
serotonergic and other modulatory interneurons all acted on the
sensory neurons and on their presynaptic terminals to enhance
transmitter release from their presynaptic terminals. We could
now ask for the first time: Was cAMP directly involved in
facilitation? In 1976, Marcello Brunelli could take advantage of
the size of the Aplysia neurons and inject cAMP directly
into the presynaptic sensory cell and thereby find a clear
enhancement of synaptic transmission. This cAMP-induced
enhancement paralleled the enhancement produced by serotonin or
tail stimulation.

I now began to interact with Paul
Greengard, who was demonstrating that cAMP produced its actions
in the brain through the cAMP-dependent protein kinase, or PKA.
In 1980, Schwartz, Castellucci, and I collaborated with
Greengard. We injected a purified catalytic subunit of bovine PKA
into presynaptic sensory neurons and found that it simulated the
actions of cAMP or serotonin. Moreover, we could block the
actions of serotonin by injecting into the sensory neuron the
specific peptide inhibitor of PKA, protein kinase inhibitor PKI.
With Steven Siegelbaum we next began to define some of the
targets of PKA and focused on one target, a novel K+ channel.
Steve showed that this channel is closed by serotonin and by PKA
and that this closure is achieved in a manner consistent with the
channel being phosphorylated directly by PKA.

The Howard Hughes Medical Institute and
the molecular analysis of long-term memory
Just before I arrived at Columbia, Arnold Kriegstein, an
M.D.-Ph.D. student, succeeded in culturing embryonic
Aplysia in the N.Y.U. laboratory, a quest which had
intrigued biologists and eluded their efforts for almost a
century. Most of us who were there will not readily forget
Kriegstein's extraordinary in-house seminar in December, 1973
when he first described his discovery that the red seaweed
Laurencia pacifica is required to trigger metamorphosis
from a free-swimming veliger larva to a small crawling snail, a
discovery that allowed him to show the first pictures of the
beautiful tiny post-metamorphic juvenile Aplysia. I
remember saying to myself. "Babies are always so beautiful!"
Kriegstein's work opened up the study of development and cell
culture in Aplysia.

Because we now had young animals at all stages of development,
we at last had the essential requirements for the generation of
dissociated cell culture. This was taken on by Sam Schacher and
Eric Proshansky. With the help of Steven Rayport (another M.D.-Ph.D.
student at Columbia University), Schacher soon succeeded in culturing
the individual sensory neurons, motor neurons, and serotonergic
neurons of the gill-withdrawal reflex. The development of the culture
system coincided with two other events that allowed me to begin
studying the molecular mechanisms of long-term memory storage. The
first was my encounter with Richard
Axel and my collaboration in 1979, with him and with Richard
Scheller, who became a joint post-doctoral fellow. The second was
my being recruited to become a senior investigator at the Howard
Hughes Medical Institute.

Axel and Scheller's success in 1982 in
cloning the gene encoding the egglaying hormone in Aplysia
seeded Axel's long-term interest in neurobiology and gave me not
only a wonderful friend but also an exposure to the methods of
recombinant DNA and modern molecular biology. The very next year,
in 1983, Donald Fredrickson, the newly appointed President of the
Howard Hughes Medical Research Institute, asked Schwartz, Axel,
and me to form the nucleus of a Howard Hughes Medical Research
Institute at Columbia devoted to molecular neural science. The
Howard Hughes Medical Research Institute gave us the opportunity
to recruit from Harvard both Tom Jessell and Gary Struhl, as well
as to keep Steven Siegelbaum at Columbia.

My first goal on becoming a Highes
Investigator was to examine the molecular mechanisms underlying
the synaptic changes that parallel long-term memory storage. In
1885, Herman Ebbinghaus transformed speculation about memory into
a laboratory science by having subjects memorize lists of
nonsense syllables. In this way Ebbinghaus generated two basic
principles about memory storage. First, he found that the
transition from short-term memory to long-term memory is graded;
practice makes perfect. Second, he anticipated the existence of a
fundamental distinction between short- and long-term memory.

What, then, was the molecular basis for
this fundamental distinction between short- and long-term memory?
As we have seen, in the mid-1960s Flexner and Agranoff examined
this distinction biochemically and found that inhibitors of
protein synthesis disrupt long-term memory without adversely
affecting learning, or short-term memory. We found that long-term
sensitization in Aplysia is similarly dependent on protein
synthesis, whereas short-term sensitization is not. These
findings illustrated the generality of the distinction between
short-term and long-term memory processes for both invertebrates
and vertebrates. In each case spaced repetition of the learning
stimulus acts to transform a transient memory into a more stable
(long-term) form by means of a process that depends on new
protein synthesis. But how this occurred was a mystery.

We had earlier found in Aplysia that
long-term sensitization involved a persistent increase in the
strength of the same synaptic connection altered by the shortterm
process - the connections between the sensory and motor neurons
of the gill-withdrawal reflex. To study this process more
effectively we turned to dissociated cell culture and found that
we could reconstitute both short- and long-term synaptic
facilitation in a culture consisting of only a single sensory
neuron and a single motor neuron. We did this together with Sam
Schacher, Philip Goelet, and Pier Giorgio Montarolo by applying
either one or five brief spaced pulses of serotonin to the
sensory neuron and motor neuron in the culture dish. Much like
behavioral long-term memory, the long-term synaptic changes
required new protein synthesis while the short-term changes did
not. Thus, we had trapped the protein synthesis-dependent
component of memory storage in the elementary synaptic connection
between two identified cells. We now could address directly the
question: Why is protein synthesis required for long-term and not
short-term facilitation? What are the molecular steps that switch
on long-term facilitation and, once switched on, how is it
maintained?

We next found that steps for new proteins
are activated by a cascade of genes initiated by the
cAMP-dependent protein kinase. With repeated application of
serotonin, PKA translocates to the nucleus and in so doing
activates the MAP kinase (mitogen activated protein kinase),
another kinase often recruited for growth. Thus, one of the
functions of repeated stimulation was to cause both kinases to
move into the nucleus. Pramod Dash and Binyamin Hochner and later
Cristina Alberini, Mirella Ghirardi, and Dusan Bartsch provided
the first evidence that in the nucleus, these kinases act on a
gene regulator called CREB-1 (the cAMP response
element binding proteins) to initiate a cascade of
gene actions. With David Glanzman and Craig Bailey, we found that
the CREB-mediated gene cascade which triggers the synthesis of
new protein is required for the growth of new synaptic
connections and it is the formation of these new synapses that
sustains the long-term change.

The requirement for transcription in
long-term facilitation explained why long-term memory requires
the synthesis of new proteins. However, this requirement now
posed a cell-biological puzzle: if long-term synaptic change
relies on the activation of genes in the nucleus, that means
there is ready communication between the nucleus and the synapse.
If that is so, must all such long-lasting changes in the
signaling ability of the neuron be cell-wide? Or can long-term
synaptic changes be restricted to individual synapses.
Experiments by Kelsey Martin, based on a beautiful new cell
culture system she developed, revealed that individual synapses
or groups of synapses within a cell can be modified
independently.

A return to the hippocampus: genetically
modified mice and the study of complex spatial memory
storage
In our studies in Aplysia we focused on the simplest forms
of memory, called implicit (or procedural) memory. These memories
are concerned with the unconscious recall of perceptual and motor
skills and do not require a hippocampus. The hippocampus is
involved in explicit (or declarative) memory, memory for people,
objects, or places, memories that require conscious participation
for recall. For years I tried to encourage people who left my lab
to turn their attention to the hippocampus, but to no avail.
Finally in 1990, when I reached my 60th birthday, I returned to
the study of the hippocampus myself. I was emboldened to do so in
great part because of the development of methods for inserting
and for knocking out individual genes in mice. This work made it
clear to me that mice offered a superb genetic system for
examining the role of individual genes in synaptic modification
on the one hand, and intact behavior - explicit memory storage -
on the other. Mice have a well developed medial temporal lobe and
hippocampus, and these are important for explicit memory of
objects and space. Moreover, in 1972, Tim Bliss and Terje Lomo in
Per Andersen's laboratory in Oslo, had discovered that
electrically stimulating any one of the three major pathways in
the hippocampus gives rise to a synaptic facilitation, called
long-term potentiation or LTP. We were interested in two
questions: (1) What are the molecular signaling pathways that are
important for LTP? (2) Is LTP important for explicit memory
storage? In the move to genetically modified mice, the
contributions of Seth Grant and Mark Mayford were particularly
influential.

Grant was the driving force in our first
studies, in which we showed a role for nonreceptor tyrosine
kinases in long-term potentiation, and in spatial memory in the
hippocampus. Mayford's critical thinking became important
somewhat later, as we began to realize the limitations in the
first generation of genetically modified mice. The limitations
stimulated Mayford to develop regionally restricted promoters
that limited the expression of genes to only certain regions of
the brain, and methods for controlling the timing of gene
expression. Those two technical advances by Mayford proved
important in allowing us, and Susumu Tonegawa (whose laboratory
was now also focusing on studying memory in genetically modified
mice), to generate mice whose phenotypes were more specific and
in whom a genetic defect could be more readily interpreted than
in the first generation of genetically modified mice because the
defect could be related, somewhat more directly to specific
synaptic changes and to behavior. Over the next few years
Mayford, Ted Abel, Mark Barad, Isabelle Mansuy, Chris Pittenger,
Amy Chen, and Angel Barco created a number of regionally
restricted and regulated transgenic animals that allowed us to
examine the role of the PKA- CREB-1 and CREB-2 and the protein
synthesis-dependent transcriptional switch within the
hippocampus, and to find that it was quite similar in principle
to what we had encountered in Aplysia. Our lab and those
of Alcino Silva and Dan Storm found that the cAMP, PKA, and CREB
switch were required for long-term forms of synaptic plasticity
in the hippocampus, was also required for spatial memory.

A molecular approach to the cognitive
map of space in the hippocampus: steps toward a molecular biology
of attention
With this background information about genes, LTP, and spatial
memory, we now could ask a deeper question: How does an animal
learn about extrapersonal space? Why does spatial memory go awry
with defects in PKA signaling? What is the function of the
transcriptional switch? To address these questions, we turned to
studying how space is represented in the hippocampus.

One of the key insights to emerge from the
study of higher cognitive functions is that each perceptual or
motor act has an internal or neural representation in the brain.
These representations can be either simple or complex. The
simplest internal representations are those evident in the
sensory systems where the afferent fibers are arranged as
topographic maps of the receptor surface. These are the
representations which Wade Marshall, my former mentor at the NIH,
had discovered in the 1930s and early 1940s. Marshall showed that
this map is most clearly evident in the neural representation of
personal space, the representation of touch. The neural
representation of the space surrounding the body, the
extrapersonal space, is far more complex. Here the
representation is not topographical but encoded in the pattern of
firing of cells that do not have any specific topographic
relation to one another with respect to the receptor surface.
Thus, adjacent cells need not encode adjacent regions of
extrapersonal space.

This representation was discovered in 1971,
by John O'Keefe at University College London, who made the brilliant
observation that the hippocampus has a cognitive map - a complete
representation of extrapersonal space. O'Keefe discovered that
all the pyramidal cells in the hippocampus, the very same cells
that are used to study long-term potentiation have, as a natural
function in the intact animal, the ability to encode space. He
found that when an animal moves around in a familiar environment,
different pyramidal cells in the hippocampus fire as the animal
traverses different regions of the environment. This tendency is
so marked that O'Keefe referred to the pyramidal cells as place cells. Some place cells may fire only when the
animal's head enters one position in a given space. Other
pyramidal cells will fire when the animal's head enters another
position in the same space. Thus, a mouse's brain breaks up the
space in which it walks into many small overlapping fields, and
each field is assigned to specific cells in the hippocampus,
forming a spatial map of the animal's surroundings. When the
animal enters a new environment, a new place map is formed within
minutes.

These observations have given rise to the
idea that the hippocampus contains a map-like representation of
the animal's current extrapersonal environment, and that the
firing of place cells in the hippocampus signals the animal's
moment-to-moment location within the environment. This spatial
map is the best-understood example of a complex internal
representation in the brain, a true cognitive map. It differs in
several ways from the classical sensory maps found by Wade
Marshall for touch, vision, or hearing. Unlike sensory maps, the
map of space is not topographic, that is, neighboring cells in
the hippocampus do not represent neighboring regions in the
environment. Furthermore, a place cell will fire in the same
place regardless of what the animal is looking at. Moreover, the
firing of place cells can persist after pertinent sensory cues
are removed and even in the dark. Thus, although the activity of
a place cell can be modulated by sensory input, it is not
determined by sensory input as is the case for the activity of
neurons in a sensory system. It appears that the place cells do
not map the current sensory input, but the location where the
animal thinks it is in space.

Place fields are formed in minutes, and
once formed the map to which they contribute can remain stable
for weeks. It struck me in 1995 that formation of this internal
representation - this cognitive map of space - was a learning
process and that synaptic plasticity related to LTP might have a
role in stabilizing this cognitive representation.

Although place cells have been studied
since 1971, nothing was known about the cellular or molecular
mechanisms whereby new place fields are formed, and specifically
no one had attempted to relate the biology of place cells to the
molecular mechanisms of LTP or hippocampal-based memory. To
explore this problem, I was fortunate to start a collaboration
with Robert Muller at Downstate Medical Center in Brooklyn, who
had pioneered the systematic study of place cells. This problem
was taken on by Cliff Kentros, a postdoctoral fellow in my lab,
by Naveen Agnihotri, a graduate student, and by Alex Rotenberg, a
joint student with Muller and myself. Using a combination of
pharmacological and genetic approaches, we demonstrated a link
between recruitment of PKA and protein synthesis on the one hand,
and on the other, the long-term, but not short-term
stability of the hippocampal representation of space. Thus, PKA
and protein synthesis are required for longterm memories of
extrapersonal space because that memory is based on a learned
internal representation of space whose long-term stability
requires PKA and new protein synthesis.

This raised a final question: Explicit
memory in humans differs from implicit memory in requiring
conscious attention for recall. How does conscious attention come
to bear on explicit memory? Indeed, how can one study
consciousness in the mouse? In the course of our work on place
fields, Kentros, Agnihotri, Hawkins, and I found that the
long-term stability of the place field map correlated strongly
with the degree to which the animal was required to attend to its
environment. This demonstrates that, rather than being an
implicit, automatic, process, the long-term recall of a stably
formed place cell map requires the mouse to attend to its
environment, as would be expected for explicit memory in human
beings. The finding that attention, the recruitment of PKA, and
new protein synthesis are required to form and recall a stable
map in the mouse has opened up a molecular biological approach to
an attentional process.

From psychoanalysis to Aplysia to the
role of attention in the cognitive representation of
extrapersonal space
During the past 10 years my career has begun to come full circle.
From an initial interest in the complex cognitive problems of
psychoanalysis and memory storage, my research on memory led me
first to the mammalian hippocampus, which proved too difficult as
a first step and forced me to take a more reductionist approach
and study initially the simplest forms of memory in
Aplysia, and then, only much later, the more complex forms
of memory in mice. I found that despite important differences in
detail, simple implicit and explicit memories have a similar
short- and long-term storage form. In each form, short-term
storage requires covalent modification of pre-existing proteins
leading to the alteration of pre-existing synaptic connections,
whereas long-term memory storage requires gene activation, new
protein synthesis, and the growth of new synaptic
connections.

In the course of this work we began to
explore how explicit memory storage for space affects the
internal representation of space. We found that on the level of
internal representation the storage mechanisms for explicit
memory are similar to those in human beings in requiring
attention. Attention is a component of conscious response,
perhaps the great challenge of all research on mental processes.
It thus seems likely that in future decades, the study of memory,
perhaps even in mice, is likely to allow molecular insights into
even the deepest problems of human behavior.

A personal perspective
Although doing research on Aplysia and the hippocampus and
discussing science with colleagues in my lab have given me the
greatest intellectual satisfactions, I have loved teaching and
have learned a great deal from lecturing to medical and graduate
students. It was in the context of the neural science course at
Columbia that the idea arose of doing a textbook, Principles
of Neural Science. In college and medical school I was never
a good note-taker. I always preferred sitting back, enjoying the
lecture, and just scribbling down a few words here and there.
When I came to Columbia to develop the neural science course, I
was struck by how much energy students were devoting to writing
out every single word of lectures, and I wanted to help them get
over that. I therefore encouraged the faculty to provide a
syllabus for each lecture, and with time I edited the syllabus,
added figures to it and improved it. Then Jimmy Schwartz and I
decided that the syllabus was becoming sufficiently useful that
we might make a textbook out of it. Our textbook was the first
attempt to bridge cell and molecular biology to neural science
and neural science to behavior and clinical states. The response
to the first edition was so gratifying that we made an effort to
make the book better and more complete. With the second edition,
not only students but also scientists began to regard our
textbook as useful. With the help of Tom Jessell, we further
improved the third and fourth editions. The widespread reception
of this book, both in the United States and abroad, has been a
source of deep satisfaction to me and to the other
contributors.

Outside of our work and our family, Denise
and I enjoy the visual arts and classical music, especially
opera. Our interest in both of these activities is greatly
enriched by having within easy reach of our home the great
museums and galleries of Manhattan as well as the Metropolitan
Opera. We also are inveterate - I am tempted to say
addicted - collectors of art and antiques. We have lived
for 36 years in a now 150-year-old house in the Riverdale section
of the Bronx, with wonderful views of the Hudson River and the
Palisades. We collect French art nouveau furniture, vases, and
lamps, an interest that originated with Denise and her mother,
and graphic art of the Austrian and German Expressionists, an
interest which originated with me. As I write this, I am
beginning to suspect that our collecting may well be an attempt
to recapture a part of our hopelessly lost youth.

In the course of my career I have incurred
many debts both personal and scientific. First and foremost I owe
an enormous personal debt to my parents and my brother Lewis. My
parents were able in mid-life to relocate to a foreign country -
my father spoke not a word of English when he first arrived in
New York - and to create a new life for themselves and their
sons. My parents not only succeeded in establishing themselves in
their small store in Brooklyn, but were sufficiently successful
to support me through college and medical school. They were so
occupied with their store that throughout their life in America
they did not share in the cultural life of New York, which Lewis
and I were beginning to enjoy. Despite their constant labor they
were always extremely optimistic and supportive of us, and never
tried to dictate decisions about my work or play. Lewis was also
an enormous influence on me in my early years, and my interest in
classical music and my joy in learning were importantly
influenced by him. While a graduate student at Brown University
writing his dissertation in linguistics and Middle High German,
he was called to service as an intelligence officer in the Korean
War. He and his wife, Elise, went first in 1951 to Germany and
then in 1953 to Paris, France, where he had a position as a
civilian in Air Force Intelligence. He so enjoyed his life in
France, that he lost his interest in an academic life and stayed
in France for 13 years, where he and Elise raised five children.
He eventually returned to the United States and finished his
career in a series of administrative positions, in the Health
Department of the City of New York. He died in 1979, at age 54 of
a recurrence of a cancer of the kidney, which we all thought had
been successfully removed when it first presented 10 years
earlier.

Second, I have been privileged to enjoy a
wonderfully supportive, endlessly interesting, and stable family
life with Denise, my partner, best friend, and most honest critic
for now 45 years. Throughout our life together she has
consistently encouraged my love of research and supported my
scientific aspirations. Denise is a professor in the Department
of Psychiatry and in the School of Public Health at Columbia
University, and has pioneered the study of drug abuse in
adolescence. Her work on the epidemiology of drug abuse has
become the basis of the current understanding of the
developmental sequence whereby adolescents become involved in
drugs. I am also greatly in debted to our two children, Paul and
Minouche, for the joy they gave Denise and me while growing up
and the satisfaction they have given us in seeing what principled
and interesting people they have become and how thoughtful they
are as parents to their own children. Our son Paul majored in
economics at Haverford College and graduated from the Columbia
Business School. He now manages a set of investment funds at
Dreyfus-Mellon. Paul is married to Emily Kaplan, an interior
designer; they live in Scarsdale, N.Y. and have two daughters,
Allison (born on January 5, 1992) and Libby (born on October 14,
1995). Our daughter Minouche went to Yale College and Harvard Law
School. She practices public interest law in San Francisco
specializing in women's rights and family violence. Minouche is
married to Rick Sheinfield, also a public interest lawyer, and
they have a son, Izak (born on November 10, 1998) and a daughter,
Maya (born on March 12, 2001).

In retrospect it seems a very long way for
me from Vienna to Stockholm. My timely departure from Vienna made
for a remarkably fortunate life in the United States. The freedom
that I have experienced in America and in its academic
institutions made Stockholm possible for me, as it has for many
others.

Postscripts: a Curriculum
Vitae
I began my academic career at the Harvard Medical School, where
from 1963 to 1965, I was an instructor in the Department of
Psychiatry. In 1965, I moved to New York University as associate
professor where, together with Alden Spencer and James Schwartz,
we developed the first group in the country devoted to both
cellular neurobiology and behavior. At the time I was recruited
to N.Y.U., Denise was recruited to the Columbia University
College of Physicians and Surgeons, where she gradually rose to
the rank of professor.

In 1974, Harry Grundfest retired and I was
recruited to Columbia to replace him. At Columbia I was the
founding director of the Center for Neurobiology and Behavior. In
1983, I became a University Professor at Columbia. In 1984, I
resigned as director of the Center to become a senior
investigator at the newly formed Howard Hughes Medical Research
Institute at Columbia.

Since 1974, I have been a member of the
National Academy of Sciences USA. Later I
became a member of the National Science Academies of Germany and
France, the American Academy of Arts and Sciences, the American
Philosophical Society, the National Institute of Medicine, and
most recently, Germany's Orden Pour Le Mérite für
Wissenschaften und Künste. Being invited to join the Orden
was for me a particularly great honor. The collection of scholars
and scientists in the Orden is extraordinary; as an extra bonus
it includes old friends such as the great German historian Fritz
Stern, and a sterling group of biologists including Max Perutz, Christiane
Nüsslein-Volhard, Bert Sakmann, Erwin Neher, Walter
Gehring, Charles Weissman, and Robert Weinberg.

I have been awarded the Lester N. Hofheimer
Prize for Research of the American Psychiatric Association
(1977), the Karl Spencer Lashley Prize in Neurobiology from the
American Philosophical Society (1981), the Dickson Prize in
Biology and Medicine from the University of Pittsburgh (1982), the Albert
Lasker Award (1983), the Rosenstiel Award of Brandeis University
(1984), the Howard Crosby Warren Medal by the Society of
Experimental Psychologists (1984), the American Association of
Medical Colleges Award for Distinguished Research in the
Biomedical Sciences (1985), the Gairdner International Award of
Canada for Outstanding Achievement in Medical Science (1987), the
National Medal of Science (1988), the J. Murray Luck Award for
Scientific Reviewing from the National Academy of Sciences
(1988), the American College of Physicians Award in Basic Science
(1989), the Robert J. and Claire Pasarow Foundation Award in
Neuroscience (1989), the Bristol-Myers Squibb Award for
Distinguished Achievement in Neuroscience Research (1991), the
Warren Triennial Prize from the Massachusetts General Hospital
(1992), the Harvey Prize of the Technion in Haifa (1993), the
Stevens Triennial Prize from Columbia University (1995), the Dana
Award (1997), the Gerard Prize of the Society of Neuroscience
(1997), the Wolf Prize of Israel (1999), and the Dr. A.H.
Heineken Prize for Medicine from the Royal Netherlands Academy of
Arts and Sciences in Amsterdam (2000).

I have received honorary degrees from nine
universities, including three European universities: the
University of Vienna, Edinburgh, and Turin. Surprisingly, the first
honorary degree I received, in 1983, was from the Jewish
Theological Seminary in New York. I was thrilled that they would
even know of my work. I suspect they learned of that from my
colleague Mortimer Ostow, one of the psychoanalysts who first
stirred my interest in relating psychoanalysis and the brain. My
father had already died but my mother came to the graduation
ceremony, and in his introductory remarks Gerson D. Cohen, the
chancellor of the seminary, referred to my having received a good
Hebrew education at the Yeshiva of Flatbush, an acknowledgement
which filled my mother's Jewish heart with pride. As this
recitation makes clear, I also owe a profound intellectual debt
to my scientific teachers - Harry Grundfest, Dominick Purpura,
Wade Marshall, and Ladislav Tauc - who tolerated my naivete and
encouraged my brashness. I also benefited greatly from Steve
Kuffler's sage insight and advice and from Alden Spencer's
generous friendship. I also am indebted to the extraordinary
collection of colleagues, fellows, and students that I have had
the privilege of interacting and collaborating with and whose
individual contributions I describe in more detail in my Nobel
Lecture. Finally, I am deeply grateful to Columbia University and
the Howard Hughes Medical Research Institute, two great
institutions that have created open environments supportive of
scholarship and research.

This autobiography/biography was written
at the time of the award and later published in the book series Les
Prix Nobel/Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted
by the Laureate.

For more biographical information, see: Kandel, Erich
R., In Search of
Memory: The Emergence of a New Science of Mind. W.W. Norton, New York,
2006.